The craniofacial skeleton requires the coordination of developmental processes that are regulated by a number of different signaling pathways. Disruption of these signaling pathways can lead to craniofacial disorders in newborns and cancer in adults. My project examines the molecular mechanisms employed by Endothelin-1 (Edn1) that signals one of these pathways. Zebrafish ednl mutants, studied in the Kimmel lab, exhibit severe defects in the ventral pharyngeal arch derived skeletal structures that include reduction of ventral pharyngeal arch cartilages, fusion between cartilages, homeotic transformation, and changes in cartilage shape. The signaling mechanisms employed by Edn1 remain unclear, however, several genes have been identified through forward mutagenesis screens that provide clues to the Edn1 pathway, one such gene is plcps. The plcps mutant exhibits similar craniofacial defects to ednl mutants, supporting a role for Plcps to transduce the Ednl signal to promote pharyngeal arch growth and morphogenesis. I propose to 1) determine if Ednl requires Plcps to regulate cell proliferation and cell death of neural crestderived cells, by measuring cell proliferation and cell death in embryos lacking ednl and plcp3; 2) determine if Plcps is required to link the aPKC/Par complex with regulators of the actin cytoskeleton to promote convergence-extension of the pharyngeal arches by disrupting each component and performing geometric morphometric analysis; and 3) use forward mutagenesis screens to identify new genes that function in the Ednl pathway. This fellowship will establish my career using the zebrafish craniofacial development model to investigate how the de-regulation of signaling pathways can lead to developmental disorders and disease. My research will provide data that will increase our understanding how Ednl initiates these developmental pathways, which will help create better strategies to combat diseases, such as cancer, that result when signaling is disrupted or de-regulated. [unreadable] [unreadable] [unreadable]